Chiral N-phosphonyl imine chemistry: asymmetric additions of glycine enolate to diphenyl diamine-based phosphonyl imines

Diphenyl diamine-based phosphonyl imines attached by the N-isopropyl group in the auxiliary have been synthesized in good yields under convenient reaction conditions. These new chiral N-phosphonyl imines can react with glycine enolate smoothly to give chiral α-β diamino esters in good yields (72%–90%) and up to excellent diastereoselectivity (>99:1 dr). By treatment with HBr, the chiral auxiliary can be readily removed. The absolute structure has been unambiguously determined by converting a product to a known sample.     

Chiral boron enolate aldol additions to chiral aldehydes

We have examined the double-diastereodifferentiating aldol addition reactions of chiral enolborinate 1a with chiral aldehydes leading to the corresponding aldol adducts with excellent levels of 1,5-anti diastereoselection.     

Chiral N-phosphonyl imine chemistry: asymmetric 1,2-additions of allylmagnesium bromides

Chiral N-phosphonyl homoallylic amines were synthesized by the reaction of allylmagnesium bromide with chiral N-phosphonyl imines. The C₂-symmetric chiral N-phosphonyl group was optimized for this reaction. Excellent yields and good diastereoselectivities were obtained for eight examples.     

Chiral propionate enolate equivalent for stereoselective additions to symmetrical ketones

The copper enolate derived from (η⁵-C₅H₅)Fe(CO)(PPh₃)COCH₂CH₃ reacts stereoselectively with symmetrical ketones to generate RR,SS-α-methyl-β-hydroxy acyl complexes which on decomplexation liberate the corresponding β-hydroxy acids.     

Chiral N-phosphonyl imine chemistry: new reagents and their applications for asymmetric reactions

Novel chiral N-phosphonyl imines 2 have been designed and synthesized using chiral N-phosphoramide 1. These N-phosphonyl imines have been successfully utilized for asymmetric aza-Darzens reaction and asymmetric aza-Henry reaction. The C₂-symmetric chiral auxiliary tolerates oxidation, is not sensitive to racemization and can be recycled for large scale synthesis.     

Chiral counteranion-aided asymmetric hydrogenation of acyclic imines

When combined with a chiral phosphate counteranion, a chiral diamine-ligated Ir(III) catalyst displayed excellent enantioselectivities in the asymmetric hydrogenation of a wide range of acyclic imines, affording chiral amines in up to 99% ee.     

Enantioselective alkylation of enolate derived from glycine influence of the imine moiety

Optically active alanine was obtained by asymmetric one carbon transfer reaction. Variation of the nature of the imine moiety in the enantioselective alkylation of Schiff bases derived from glycine caused the enantiomeric excess to shift from 0 to 70 %.     

Co-catalyst enhancement of enantioselective PTC Michael additions involving glycine imines

In this Letter we demonstrate that the use of 2,4,6-trimethylphenol (mesitol) as a co-catalyst facilitates highly enantioselective addition of benzophenone glycine imine tert-butyl ester to a range of Michael acceptors.     

Organocatalytic asymmetric 1,6-additions of beta-ketoesters and glycine imine

The first organocatalytic enantioselective 1,6-addition of beta-ketoesters and benzophenone imine to electron-poor delta-unsubstituted dienes using cinchona alkaloids under phase-transfer conditions is demonstrated. The scope of the reaction for the beta-ketoesters is outlined for reactions with different delta-unsubstituted dienes having ketones, esters, and sulfones as electron-withdrawing substituents giving the corresponding optically active products in good yields and enantioselectivities in the range of 90-99% ee. The 1,6-addition also proceeds with a number of cyclic beta-ketoesters having different ring sizes, ring systems and substituents in high yields and enantioselectivities. The potential of this new organocatalytic 1,6-addition for beta-ketoesters is demonstrated by a two-step synthesis of the bicyclo[3.2.1]octan-8-one structure, a bicyclic bridged skeleton occurring in a variety of natural compounds. Benzophenone imines also undergo the organocatalytic asymmetric 1,6-addition to the activated dienes in high yields and with enantioselectivities from 92% to 98% ee, except in one case. The synthetic utility of this asymmetric reaction is demonstrated by the two-step transformation of the allylated alpha-amino acid derivative to highly attractive optically active pyrrolidines.     

Asymmetric synthesis of beta-amino acid derivatives incorporating a broad range of substitution patterns by enolate additions to tert-butanesulfinyl imines

Addition of Ti(Oi-Pr)(3) ester enolates to tert-butanesulfinyl aldimines and ketimines provided beta-substituted, alpha,beta- and beta,beta-disubstituted, alpha,beta,beta- and alpha,alpha,beta-trisubstituted, and alpha,alpha,beta,beta-tetrasubstituted beta-amino acid derivatives in high yields and with high diastereoselectivites. The N-sulfinyl-beta-amino ester products were further employed as versatile intermediates for both standard solution-phase and solid-phase synthetic transformations, including the synthesis of beta-peptide foldamers.     

Highly enantioselective synthesis of atropisomeric anilide derivatives through catalytic asymmetric N-arylation: conformational analysis and application to asymmetric enolate chemistry

In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)(2) catalyst, N-arylation (aromatic amination) of various o-tert-butylanilides with p-iodonitrobenzene proceeds with high enantioselectivity (88-96% ee) to give atropisomeric N-(p-nitrophenyl)anilides having an N-C chiral axis in good yields. Atropisomeric anilide products highly prefer to exist as the E-rotamer which has trans-disposed o-tert-butylphenyl group and carbonyl oxygen. The application of the present catalytic enantioselective N-arylation to an intramolecular version gives atropisomeric lactam derivatives with high optical purity (92-98% ee). The reaction of the lithium enolate prepared from the atropisomeric anilide and lactam products with various alkyl halides gives alpha-alkylated products with high diastereoselectivity (diastereomer ratio = 13:1 to 46:1).     

Chiral phosphine-free Pd-mediated asymmetric allylation of prochiral enolate with a chiral phase-transfer catalyst

[reaction: see text]. A chiral phase-transfer catalyst has been applied to the asymmetric allylation of the tert-butyl glycinate-benzophenone Schiff base with various allylic acetates for the first time to give the allylated products in good yields and with comparable to higher enantioselectivity than for asymmetric alkylation at the same temperature (91-96% ee) without any chiral ligands for coordinating to the palladium.     

Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

In the presence of (R)-SEGPHOS-Pd(OAc)₂ catalyst, the intramolecular N-arylation of ortho-tert-butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89-98% ee) to give optically active atropisomeric lactams having an N-C chiral axis. MPLC purification of the enantio-enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric lactam with various alkyl halides gave α-substituted and α,α-disubstituted lactam products with high diastereoselectivity. α-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.     

Stereodivergency in catalytic asymmetric conjugate addition reactions of glycine (ket)imines

Stereodivergent catalytic asymmetric conjugate reactions of glycine (ket)imines with nitroalkenes have been achieved using various chiral catalyst systems derived from a multidentate amino alcohol (1). The stepwise nature of the [3 + 2] cycloaddition reactions of N-metalated azomethine ylides has also been demonstrated by highly enantio- and diastereoselective syntheses of exo-5 and endo-8 from the respective syn-4 and anti-7 conjugate addition products in a one-pot tandem fashion.     

A convenient method for asymmetric alkylation of glycine imine esters using solid supports

Asymmetric alkylation of butyl glycinate-benzophenone Schiff base proceeded smoothly on clays and alumina at room temperature to afford alkylated products in high yields and good enantioselectivities.     

Direct catalytic asymmetric Mannich-type reactions of isomerizable aliphatic imines: chemoselective enolate formation from a hydroxyketone by a Zn-catalyst

A direct catalytic asymmetric Mannich-type reaction of isomerizable aliphatic imines is described. A Et₂Zn/(S,S)-linked-BINOL complex was suitable for chemoselective enolate formation from a hydroxyketone in the presence of isomerizable aliphatic N-diphenylphosphinoyl imines. The reaction proceeds smoothly and β-alkyl-β-amino-α-hydroxyketones were obtained in good yield and high enantioselectivity (up to 99% ee), albeit in modest to low diastereoselectivity.     

Synthesis of tertiary beta-hydroxy amides by enolate additions to acylsilanes

The synthesis of tertiary beta-hydroxy amides from acylsilanes, acetamides, and electrophiles is described. The addition of amide enolates to acylsilanes generates beta-silyloxy homoenolate reactivity by undergoing a 1,2-Brook rearrangement. These unique nucleophiles formed in situ can then undergo smooth addition to alkyl halides, aldehydes, and ketones. Enolates derived from amides are crucial for the success of this process since ketone enolates suffer from internal return of the beta-carbanion onto the carbonyl carbon. The use of optically active amide enolates delivers beta-hydroxy amide products with good levels of diastereoselectivity (>/=10:1).